WO2013014497A1 - Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor - Google Patents
Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor Download PDFInfo
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- WO2013014497A1 WO2013014497A1 PCT/IB2011/054352 IB2011054352W WO2013014497A1 WO 2013014497 A1 WO2013014497 A1 WO 2013014497A1 IB 2011054352 W IB2011054352 W IB 2011054352W WO 2013014497 A1 WO2013014497 A1 WO 2013014497A1
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- pharmaceutically acceptable
- acceptable salt
- sulbactam
- lactamase inhibitor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention relates to antibacterial compositions and methods for preventing or treating bacterial infections.
- beta-lactam antibiotics Resistance to beta-lactam antibiotics is wide spread and a key concern.
- One of the mechanism bacteria have developed against beta-lactam antibiotics is production of several beta-lactamase enzymes, which deactivate the beta-lactam antibiotic.
- a typical beta-lactam antibiotic alone may not be effective in treating infections caused by such beta- lactamase producing bacteria.
- One alternative to treating infections caused by bacteria producing beta-lactamase enzymes is by co-administration of a beta-lactamase inhibitor with the beta-lactam antibiotic.
- the beta-lactamase inhibitor prevents deactivation of a beta-lactam antibiotic, typically by binding with the beta-lactamase enzyme.
- even the combination therapy is also proving ineffective in treating infections caused by newer ESBL strains.
- Drawz et al. (Clinical Microbiology Reviews, 2010, 23(1), pages 160-201) have reviewed developments in the area of beta-lactamase inhibition and inhibitors. Drawz et al. summarize various beta-lactamase inhibitors developed to overcome bacterial resistance. Gold et al. (The New England Journal of Medicine, 1996, 335(19), pages 1445-1453) have also reviewed the subject of antimicrobial drug resistance.
- compositions and methods for treating or preventing bacterial infections are provided.
- compositions comprising pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for increasing antibiotic effectiveness of a beta-lactam antibiotic in a subject comprising coadministering said beta-lactam antibiotic with a pharmaceutically effective amount of: (a) sulbactam or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta- lactamase inhibitor is not sulbactam.
- a pharmaceutical composition comprising pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam, exhibits unexpectedly improved antibacterial efficacy, even against highly resistant ESBL producing bacteria.
- infection includes presence of bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject.
- infection in addition to referring to the presence of bacteria also refers to normal flora, which are not desirable.
- infection includes infection caused by bacteria.
- treat refers to administering a medicament, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and/or therapeutic purposes.
- prophylactic treatment refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection.
- therapeutic treatment refers to administering treatment to a subject already suffering from infection.
- treat also refers to administering compositions or one or more of pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or inert ingredients, in order to: (i) reduce or eliminate either a bacterial infection or one or more symptoms of the bacterial infection, or (ii) retard the progression of a bacterial infection or of one or more symptoms of the bacterial infection, or (iii) reduce the severity of a bacterial infection or of one or more symptoms of the bacterial infection, or (iv) suppress the clinical manifestation of a bacterial infection, or (v) suppress the manifestation of adverse symptoms of the bacterial infection.
- a therapeutically or pharmaceutically effective amount of an antibiotic or a pharmaceutical composition is the amount of the antibiotic or the pharmaceutical composition required to produce a desired therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or in vitro studies (e.g. in agar or broth media).
- the pharmaceutically effective amount depends on several factors, including but not limited to, the microorganism (e.g. bacteria) involved, characteristics of the subject (for example height, weight, sex, age and medical history), severity of infection and the particular type of the antibiotic used.
- a therapeutically or prophylactically effective amount is that amount which would be effective to prevent a microbial (e.g. bacterial) infection.
- administration includes delivery of a composition or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate methods, which serves to deliver the composition or it's active ingredients or other pharmaceutically active ingredients to the site of the infection.
- the method of administration may vary depending on various factors, such as for example, the components of the pharmaceutical composition or the type/nature of the pharmaceutically active or inert ingredients, the site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject and a like.
- Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention includes oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
- a pharmaceutical composition that comprises more than one ingredient (active or inert) one of way of administering such composition is by admixing the ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder and a like) and then administering the dosage form.
- the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients reach beneficial therapeutic levels such that the composition as a whole provides a synergistic and/or desired effect.
- growth refers to a growth of one or more microorganisms and includes reproduction or population expansion of the microorganism (e.g. bacteria).
- the term also includes maintenance of on-going metabolic processes of a microorganism, including processes that keep the microorganism alive.
- ⁇ refers to ability of a treatment or a composition or one or more pharmaceutically active ingredients to produce a desired biological effect in a subject.
- antibiotic effectiveness refers to the ability of the composition or the beta- lactam antibiotic to prevent or treat the microbial (e.g. bacterial) infection in a subject.
- antibiotic refers to any substance, compound or a combination of substances or a combination compounds capable of: (i) inhibiting, reducing or preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to produce infection in a subject; or (iii) inhibiting or reducing ability of bacteria to multiply or remain infective in the environment.
- antibiotic also refers to compounds capable of decreasing infectivity or virulence of bacteria.
- beta-lactam antibiotic refers to compounds with antibiotic properties and containing a beta-lactam nucleus in their molecular structure.
- beta-lactamase refers to any enzyme or protein or any other substance that breaks down a beta-lactam ring.
- beta-lactamase includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta- lactam antibiotic, either partially or completely.
- beta-lactamase inhibitor refers to a compound capable of inhibiting activity of one or more beta-lactamase enzymes, either partially or completely.
- pharmaceutically inert ingredient or “carrier” or “excipient” refers to a compound or material used to facilitate administration of a compound, for example, to increase the solubility of the compound.
- Solid carriers include, e.g., starch, lactose, dicalcium phosphate, sucrose, and kaolin.
- Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils.
- subject refers to vertebrate or invertebrate, including a mammal.
- subject includes human, animal, a bird, a fish, or an amphibian.
- Typical, non-limiting examples of a “subject” includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
- pharmaceutically acceptable salt refers to one or more salts of a given compound which possesses the desired pharmacological activity of the free compound and which are neither biologically nor otherwise undesirable.
- pharmaceutically acceptable salts refer to salts that are suitable for use in contact with the tissues of human and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1- 19 (1977)), incorporated herein by reference, describes various pharmaceutically acceptable salts in details.
- Cftolozane refers to a compound also known as CXA-101 (CAS Registry No.: 689293-68-3; Chemical Name: (6R,7R)-3-[(5-amino-4- ⁇ [(2- aminoethyl)carbamoyl]amino ⁇ -l-methyl-lH-pyrazol-2-ium-2-yl)methyl]-7-( ⁇ (2Z)-2-(5- amino-l,2,4-thiadiazol-3-yl)-2-[(l-carboxy-l- methyl ethoxy)imino]acetyl ⁇ amino)-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate).
- CXA-101 has a chemical structure as given Formula (I), below:
- trans-7-oxo-6-(sulphooxy)-l,6-diazabicyclo- [3.2.1 ]-octane-2- carboxamide refers to a compound also known as Sulfuric acid, mono[(lR,2S,5R)-2-(aminocarbonyl)-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl] ester).
- trans-7-oxo-6-(sulphooxy)-l,6-diazabicyclo-[3.2.1]-octane-2-carboxamide is intended to include its pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts and its any other pharmaceutically acceptable derivative.
- beta- lactam antibiotic includes their pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts and their any other pharmaceutically acceptable derivatives.
- compositions comprising pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of: (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam.
- a method for increasing antibiotic effectiveness of a beta-lactam antibiotic in a subject comprising co- administering said beta-lactam antibiotic with a pharmaceutically effective amount of: (a) sulbactam or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta- lactamase inhibitor is not sulbactam.
- compositions and methods according to this invention use a beta-lactam antibiotic.
- any beta-lactam antibiotic (a beta-lactam antibiotic is a compound with antibiotic properties and contains a beta-lactam nucleus in its molecular structure) could be used in compositions and methods according to this invention.
- a suitable derivative of a beta-lactam antibiotic may also be used.
- suitable derivatives include pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts and a like of such beta-lactam antibiotics.
- beta-lactam antibiotics include those belonging to penicillins, penems, carbapenems, cephalosporins, and monobactams.
- Typical examples of beta-lactam antibiotics include, but are not limited to amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, epicillin, carbenicillin, ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam, sulbenicillin, clometocillin, benzathine, benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, methicillin, nafcillin, faropenem
- compositions and methods according to this invention also use sulbactam or pharmaceutically acceptable salts thereof.
- a suitable derivative of sulbactam may also be used.
- suitable derivatives include pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts and a like.
- compositions and methods according to this invention also use one or more beta- lactamase inhibitors or a pharmaceutically acceptable salt.
- a suitable derivative of beta-lactamase inhibitor may also be used.
- suitable derivatives include pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts and a like of such beta-lactamase inhibitors.
- any compound capable of inhibiting activity of one or more beta-lactamase enzymes, either partially or completely, can be advantageously used in the compositions and methods according to this invention.
- the beta-lactam antibiotic in the composition and/or methods according to the invention is selected from the group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams.
- the beta-lactam antibiotic in the composition and/or methods according to the invention is a cephalosporin antibiotic selected from the group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceifriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cef
- the beta-lactam antibiotic in the composition and/or methods according to the invention is selected from the group consisting of ceftazidime, cefepime, cefpirome, piperacillin doripenem, meropenem, imipenem, ceftaroline and ceftolozane.
- sulbactam in the composition and/or methods according to the invention is present as sulbactam sodium.
- the beta-lactamase inhibitor in the composition and/or methods according to the invention is at least one selected from tazobactam, clavulanic acid and trans- 7-oxo-6-(sulphooxy)-l,6-diazabicyclo-[3.2.1]-octane-2-carboxamide, or a pharmaceutically acceptable salt thereof.
- the beta-lactamase inhibitor in the composition and/or methods according to the invention is trans-7-oxo-6-(sulphooxy)-l,6-diazabicyclo-[3.2.1]- octane-2-carboxamide, or a pharmaceutically acceptable salt thereof.
- the beta-lactamase inhibitor in the composition and/or methods according to the invention is sodium salt of trans-7-oxo-6-(sulphooxy)-l,6- diazabicyclo- [3.2.1 ] -octane- 2-carboxamide.
- compositions according to this invention can exist in various forms.
- the pharmaceutical composition is in the form of a powder or a solution.
- the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration.
- a compatible reconstitution diluent includes water.
- the pharmaceutical compositions according to the invention are in the form of a frozen composition that can be diluted with a compatible diluent prior to parenteral administration.
- compositions according to the invention are in the form ready to use for parenteral administration.
- beta-lactam antibiotic is present in the composition in an amount from about 0.01 to about 10 gm.
- sulbactam is present in the composition in an amount from about 0.01 to about 10 gm.
- beta-lactamase inhibitor is present in the composition in an amount from about 0.01 to about 10 gm. Amounts below or above these ranges may also be employed, if desired.
- the amount of a beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor that may be administered to a subject may vary depending on specific requirements.
- beta-lactam antibiotic is administered in an amount from about 0.01 to about 10 gm per day.
- sulbactam is administered in an amount from about 0.01 to about 10 gm per day.
- a beta-lactamase inhibitor is administered in an amount from about 0.01 to about 10 gm per day. Amounts below or above these ranges may also be administered, if desired.
- the pharmaceutical composition and/or other pharmaceutically active ingredients may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site.
- the method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, the microorganism (e.g. bacteria) involved, severity of infection, age and physical condition of the subject.
- compositions to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
- compositions according to the invention can be formulated into various dosage forms wherein the active ingredients (e.g. beta-lactam antibiotic, sulbactam and beta- lactamase inhibitor) may be present either together (e.g. as an admixture) or as separate components.
- active ingredients e.g. beta-lactam antibiotic, sulbactam and beta- lactamase inhibitor
- the various ingredients in the composition are formulated as a mixture, such composition can be delivered by administering such a mixture.
- the composition or dosage form wherein the ingredients do not come as a mixture, but come as separate components, such composition/dosage form may be administered in several ways. In one possible way, the ingredients may be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components or the ingredients (active or inert) may be separately administered (simultaneously or one after the other) in appropriate proportion so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.
- the active ingredients may be administered to a subject in several ways depending on the requirements.
- the active ingredients are admixed in appropriate amounts and then the admixture is administered to a subject.
- the active ingredients are administered separately. Since the invention contemplates that the active ingredients agents may be administered separately, the invention further provides for combining separate pharmaceutical compositions in kit form.
- the kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients.
- kits may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like.
- the kit comprises directions for the administration of the separate components.
- the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals.
- the active ingredients are administered separately, they may be administered simultaneously or sequentially.
- compositions or the active ingredients according to the present invention may be formulated into a variety of dosage forms.
- dosage forms include solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs and a like.
- compositions and methods disclosed herein are useful in preventing or treating bacterial infections.
- compositions and methods disclosed herein are also effective in preventing or treating infections caused by bacteria that are considered be less or not susceptible to one or more of known beta-lactam antibiotic or their known compositions.
- Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like.
- infections that may be prevented or treated using the compositions and/or methods of the invention include: skin and soft tissue infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical, infections etc.
- compositions and methods according to the invention are also effective in preventing or treating bacterial infections that are caused by bacteria producing one or more beta-lactamase enzymes.
- the ability of compositions and methods according to the present invention to treat such resistant bacteria with typical beta-lactam antibiotics represents a significant improvement in the art.
- Table 1 details results of the activity study using cefepime (a beta-lactam antibiotic), sulbactam and NXL-104 (a beta-lactamase inhibitor), alone and in combination with each other.
- NXL-104 is sodium salt of trans-7-oxo-6-(sulphooxy)-l,6-diazabicyclo-[3.2.1]-octane- 2-carboxamide.
- each of cefepime, sulbactam and NXL-104 have much higher MIC values indicating their lower antibiotic effectiveness, when used alone.
- a combination comprising (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam, can be effectively used in preventing or treating a bacterial infection (even those being caused by bacteria producing one or more beta-lactamase enzymes) in a subject.
- compositions and methods in treating bacterial infections were studied.
- the study protocol was same as used in Example 1, except that beta-lactam antibiotic was cefpirome in place of cefepime.
- NXL-104 is sodium salt of trans-7-oxo-6-(sulphooxy)-l,6-diazabicyclo-[3.2.1]-octane-
- the overall MIC values for cefpirome in presence of sulbactam and NXL-104 are surprisingly dropped to as low as less than 0.03mcg/ml.
- a combination comprising (a) at least one beta-lactam antibiotic or a pharmaceutically acceptable salt thereof, (b) sulbactam or a pharmaceutically acceptable salt thereof, and (c) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, with the provision that the beta-lactamase inhibitor is not sulbactam, can be effectively used in preventing or treating a bacterial infection (even those being caused by bacteria producing one or more beta-lactamase enzymes) in a subject.
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Priority Applications (12)
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CA2842779A CA2842779C (en) | 2011-07-26 | 2011-10-04 | Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor |
BR112013032770A BR112013032770A2 (pt) | 2011-07-26 | 2011-10-04 | composições farmacêuticas compreendendo antibiótico beta-lactama, sulbactama e inibidor de beta-lactamase |
JP2014520742A JP5809750B2 (ja) | 2011-07-26 | 2011-10-04 | β−ラクタム抗生物質、スルバクタム及びβ−ラクタマーゼ阻害薬を含む医薬組成物 |
KR1020137032162A KR101738210B1 (ko) | 2011-07-26 | 2011-10-04 | 베타-락탐계 항생제, 술박탐 및 베타―락타마아제 저해제를 포함하는 약학 조성물 |
EP11781621.5A EP2768503A1 (en) | 2011-07-26 | 2011-10-04 | Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor |
CN201180072185.1A CN103648496B (zh) | 2011-07-26 | 2011-10-04 | 包含β-内酰胺抗生素、舒巴坦和β-内酰胺酶抑制剂的药物组合物 |
US14/114,207 US9095594B2 (en) | 2011-07-26 | 2011-10-04 | Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor |
MX2013013787A MX362683B (es) | 2011-07-26 | 2011-10-04 | Composiciones farmacéuticas que comprenden antibiótico de beta-lactama, sulbactama e inhibidor de beta-lactamasa. |
RU2014106988/15A RU2569059C2 (ru) | 2011-07-26 | 2011-10-04 | Фармацевтические композиции, содержащие бета-лактамный антибиотик, сульбактам и ингибитор бета-лактамаз |
AU2011373912A AU2011373912B2 (en) | 2011-07-26 | 2011-10-04 | Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor |
NZ617104A NZ617104A (en) | 2011-07-26 | 2011-10-04 | Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor |
ZA2013/08066A ZA201308066B (en) | 2011-07-26 | 2013-10-29 | Pharmaceutical compositions comprising beta-lactam antiboitic,sulbactam and beta-lactamase inhibitor |
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IN2125/MUM/2011 | 2011-07-26 | ||
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EP (1) | EP2768503A1 (ru) |
JP (1) | JP5809750B2 (ru) |
KR (1) | KR101738210B1 (ru) |
CN (1) | CN103648496B (ru) |
AU (1) | AU2011373912B2 (ru) |
BR (1) | BR112013032770A2 (ru) |
CA (1) | CA2842779C (ru) |
MX (1) | MX362683B (ru) |
NZ (1) | NZ617104A (ru) |
RU (1) | RU2569059C2 (ru) |
WO (1) | WO2013014497A1 (ru) |
ZA (1) | ZA201308066B (ru) |
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WO2015059629A1 (en) * | 2013-10-22 | 2015-04-30 | Wockhardt Limited | Pharmaceutical compositions comprising sulbactam and imipenem |
US9120795B2 (en) | 2013-03-14 | 2015-09-01 | Cubist Pharmaceuticals, Inc. | Crystalline form of a β-lactamase inhibitor |
US9120796B2 (en) | 2013-10-02 | 2015-09-01 | Cubist Pharmaceuticals, Inc. | B-lactamase inhibitor picoline salt |
JP2016517436A (ja) * | 2013-03-15 | 2016-06-16 | メルク シャープ アンド ドーム コーポレイション | セフトロザン抗生物質組成物 |
WO2016151543A1 (en) * | 2015-03-25 | 2016-09-29 | Wockhardt Limited | Pharmaceutical compositions comprising antibacterial agents |
JP2017508769A (ja) * | 2014-03-29 | 2017-03-30 | ウォックハート リミテッド | セフェピムまたはスルバクタムを含む医薬組成物 |
CN106794250A (zh) * | 2014-03-14 | 2017-05-31 | 沃克哈特有限公司 | 包含抗菌剂的药物组合物 |
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US10125152B2 (en) | 2013-01-10 | 2018-11-13 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
US10214547B2 (en) | 2012-12-07 | 2019-02-26 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
US10294247B2 (en) | 2014-06-11 | 2019-05-21 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
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US10376499B2 (en) | 2014-11-17 | 2019-08-13 | Entasis Therapeutics Limited | Combination therapy for treatment of resistant bacterial infections |
US10399996B2 (en) | 2015-09-11 | 2019-09-03 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
US10464952B2 (en) | 2015-12-10 | 2019-11-05 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
US10500191B2 (en) | 2015-07-09 | 2019-12-10 | Washington University | Compositions and methods of use of antibacterial drug combinations |
US10800778B2 (en) | 2016-09-16 | 2020-10-13 | Entasis Therapeutics Limited | Beta-lactamase inhibitor compounds |
US10889600B2 (en) | 2016-08-04 | 2021-01-12 | VenatoRx Pharmaceuticals, Inc. | Boron-containing compounds |
US11008346B2 (en) | 2014-06-11 | 2021-05-18 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
US11046694B2 (en) | 2017-05-08 | 2021-06-29 | Entasis Therapeutics, Inc. | Compounds and methods for treating bacterial infections |
US11267826B2 (en) | 2017-05-26 | 2022-03-08 | VenatoRx Pharmaceuticals, Inc. | Penicillin-binding protein inhibitors |
US11332485B2 (en) | 2017-05-26 | 2022-05-17 | VenatoRx Pharmaceuticals, Inc. | Penicillin-binding protein inhibitors |
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ZA201308066B (en) | 2015-01-28 |
BR112013032770A2 (pt) | 2017-02-07 |
CN103648496B (zh) | 2016-05-25 |
CA2842779A1 (en) | 2013-01-31 |
RU2569059C2 (ru) | 2015-11-20 |
KR20140053901A (ko) | 2014-05-08 |
AU2011373912A1 (en) | 2013-11-14 |
CN103648496A (zh) | 2014-03-19 |
KR101738210B1 (ko) | 2017-05-19 |
EP2768503A1 (en) | 2014-08-27 |
CA2842779C (en) | 2016-04-19 |
AU2011373912B2 (en) | 2016-09-29 |
RU2014106988A (ru) | 2015-09-10 |
US9095594B2 (en) | 2015-08-04 |
NZ617104A (en) | 2015-05-29 |
MX362683B (es) | 2019-01-31 |
US20140213566A1 (en) | 2014-07-31 |
MX2013013787A (es) | 2013-12-16 |
JP2014520878A (ja) | 2014-08-25 |
JP5809750B2 (ja) | 2015-11-11 |
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